LEARNING CENTER
DRUG DEVELOPMENT PROCESS: Stages of Drug Development

Any drug development process must proceed through several stages in order to produce a product that is safe, efficacious, and has passed all regulatory requirements.

Pacific BioLabs can assist you in this process. Our scientists can help you to determine your testing needs, and our experienced staff can perform the critical tests and studies that are necessary to win FDA approval.

To get you started, below we have provided an in-depth overview of many stages in the drug development process and necessary studies. Keep in mind this is just a guide; if you have any specific questions call Pacific BioLabs at 510-964-9000 to speak to a knowledgeable resource who can help you identify what testing you may need to perform.

Detailed Stages of Drug Development

Discovery

Discovery often begins with target identification – choosing a biochemical mechanism involved in a disease condition. Drug candidates, discovered in academic and pharmaceutical/biotech research labs, are tested for their interaction with the drug target. Up to 5,000 to 10,000 molecules for each potential drug candidate are subjected to a rigorous screening process which can include functional genomics and/or proteomics as well as other screening methods. Once scientists confirm interaction with the drug target, they typically validate that target by checking for activity versus the disease condition for which the drug is being developed. After careful review, one or more lead compounds are chosen.

Product Characterization

When the candidate molecule shows promise as a therapeutic, it must be characterized—the molecule’s size, shape, strengths and weaknesses, preferred conditions for maintaining function, toxicity, bioactivity, and bioavailability must be determined. Characterization studies will undergo analytical method development and validation. Early stage pharmacology studies help to characterize the underlying mechanism of action of the compound.

Formulation, Delivery, Packaging Development

Drug developers must devise a formulation that ensures the proper drug delivery parameters. It is critical to begin looking ahead to clinical trials at this phase of the drug development process. Drug formulation and delivery may be refined continuously until, and even after, the drug’s final approval. Scientists determine the drug’s stability—in the formulation itself, and for all the parameters involved with storage and shipment, such as heat, light, and time. The formulation must remain potent and sterile; and it must also remain safe (nontoxic). It may also be necessary to perform leachables and extractables studies on containers or packaging.

Pharmacokinetics And Drug Disposition

Pharmacokinetic (PK) and ADME (Absorption/Distribution/Metabolism/Excretion) studies provide useful feedback for formulation scientists. PK studies yield parameters such as AUC (area under the curve), Cmax (maximum concentration of the drug in blood), and Tmax (time at which Cmax is reached). Later on, this data from animal PK studies is compared to data from early stage clinical trials to check the predictive power of animal models.

Preclinical Toxicology Testing And IND Application

Preclinical testing analyzes the bioactivity, safety, and efficacy of the formulated drug product. This testing is critical to a drug’s eventual success and, as such, is scrutinized by many regulatory entities. During the preclinical stage of the development process, plans for clinical trials and an Investigative New Drug (IND) application are prepared. Studies taking place during the preclinical stage should be designed to support the clinical studies that will follow.

Acute tox studies look at the effects of one or more doses administered over a period of up to 24 hours. The goal is to determine toxic dose levels and observe clinical indications of toxicity. Usually, at least two mammalian species are tested. Data from acute tox studies helps determine doses for repeated dose studies in animals and Phase I studies in humans.

Repeated Dose Studies

Depending on the duration of the studies, repeated dose studies may be referred to as subacute, subchronic, or chronic. The specific duration should anticipate the length of the clinical trial that will be conducted on the new drug. Again, two species are typically required.

Genertic Toxicity Studies

These studies assess the likelihood that the drug compound is mutagenic or carcinogenic. Procedures such as the Ames test (conducted in bacteria) detect genetic changes. DNA damage is assessed in tests using mammalian cells such as the Mouse Micronucleus Test. The Chromosomal Aberration Test and similar procedures detect damage at the chromosomal level.

Reproductive Toxicity Studies

Segment I reproductive tox studies look at the effects of the drug on fertility. Segment II and III studies detect effects on embryonic and post-natal development. In general, reproductive tox studies must be completed before a drug can be administered to women of child-bearing age.

Carcinogenicity Studies

Carcinogenicity studies are usually needed only for drugs intended for chronic or recurring conditions. They are time consuming and expensive, and must be planned for early in the preclinical testing process.

Toxicokinetic Studies

These are typically similar in design to PK/ADME studies except that they use much higher dose levels. They examine the effects of toxic doses of the drug and help estimate the clinical margin of safety. There are numerous FDA and ICH guidelines that give a wealth of detail on the different types of preclinical toxicology studies and the appropriate timing for them relative to IND and NDA or BLA filings. (See Regulatory/Animal Welfare and at www.fda.gov/cder/guidance/index.htm.)

Bioanalytical Testing

Bioanalytical laboratory work and bioanalytical method development supports most of the other activities in the drug development process. The bioanalytical work is key to proper characterization of the molecule, assay development, developing optimal methods for cell culture or fermentation, determining process yields, and providing quality assurance and quality control for the entire development process. It is also critical for supporting preclinical toxicology/pharmacology testing and clinical trials.

Clinical Trials

Clinical studies are grouped according to their objective into three types or phases:

Phase I Clinical Development (Human Pharmacology) -
Thirty days after a biopharmaceutical company has filed its IND, it may begin a small-scale Phase I clinical trial unless the FDA places a hold on the study. Phase I studies are used to evaluate pharmacokinetic parameters and tolerance, generally in healthy volunteers. These studies include initial single-dose studies, dose escalation and short-term repeated-dose studies.

Phase II Clinical Development (Therapeutic Exploratory) - Phase II clinical studies are small-scale trials to evaluate a drug’s preliminary efficacy and side-effect profile in 100 to 250 patients. Additional safety and clinical pharmacology studies are also included in this category.

Phase III Clinical Development (Therapeutic Confirmatory) - Phase III studies are large-scale clinical trials for safety and efficacy in large patient populations. While phase III studies are in progress, preparations are made for submitting the Biologics License Application (BLA) or the New Drug Application (NDA). BLAs are currently reviewed by the FDA’s Center for Biologics Evaluation and Research (CBER). NDAs are reviewed by the Center for Drug Evaluation and Research (CDER).

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